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Case ReportA Novel Adverse Event Associated with Olaparib Therapy in aPatient with Metastatic Breast Cancer

Megan Wheelden ,1 Leah Cream,1 Jeffrey Sivik,2 and Mark Robson3

1Department of Medicine, Division of Hematology/Oncology, Penn State Hershey Medical Center, Hershey, PA, USA2Department of Pharmacy, Penn State Hershey Medical Center, Hershey, PA, USA3Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York City, NY, USA

Correspondence should be addressed to Megan Wheelden; [email protected]

Received 9 April 2018; Accepted 13 June 2018; Published 27 June 2018

Academic Editor: Raffaele Palmirotta

Copyright © 2018 Megan Wheelden et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in anymedium, provided the original work is properly cited.

Olaparib was first FDA approved for use in women with advanced ovarian cancer and germline BRCA mutations. Based on theresults of subsequent research, the use of this drug has been expanded to patients with metastatic breast cancer with germlineBRCA mutation. With the use of a relatively new medication and a larger patient population eligible for therapy, monitoring fornovel adverse events associated with therapy is important. This case represents a patient with metastatic breast cancer andgermline BRCA2 mutation who developed erythema nodosum after initiation of therapy with olaparib capsules. Hercharacteristic rash appeared shortly after starting olaparib and recurred after restarting olaparib an additional two times. Shewas treated with short courses of prednisone therapy with or without holding olaparib with resolution of her rash. The patientwas later restarted on olaparib capsules 200mg twice daily, and she more recently has been maintained on olaparib tablets300mg twice daily. On both regimens, the patient experienced only attenuated episodes of erythema nodosum that have notrequired cessation of therapy or steroid therapy.

1. Introduction

Mutations of tumor suppressor breast cancer susceptibilitygenes 1 and 2 (BRCA1 and BRCA2) are well known topredispose affected individuals to the development ofbreast and/or ovarian cancers [1]. After laboratory studiesdemonstrated effective treatment of these mutated cellswith poly(ADP ribose) polymerase (PARP) inhibitors, thesemedications were subsequently utilized in clinical trials [2].Olaparib was first approved in 2014 for the treatment ofpatients with advanced ovarian cancer with a germline BRCAmutation with progression after at least three lines of chemo-therapy [3]. This approval was based on the results of Study19 published in the New England Journal of Medicine in2012 [3, 4]. A logical extension of this successful trial wasto investigate olaparib in the treatment of breast cancer.The recently published OlympiAD trial demonstrated asignificant improvement in progression-free survival forpatients with metastatic breast cancer and germline BRCA

mutations treated with olaparib versus those who receivedstandard therapy with capecitabine, eribulin, or vinorelbine[5]. With the expansion of the patient population eligiblefor olaparib therapy, monitoring for novel adverse eventsis critical. We present a case report of such an adverseevent in a patient receiving olaparib therapy for metastaticbreast cancer.

2. Case Presentation

A 45-year-old female with a history of metastatic breast can-cer presented with an erythematous rash in her bilaterallower extremities. She was diagnosed approximately fouryears previously with estrogen and progesterone receptorpositive, HER-2-negative breast cancer with involvement oftwelve axillary lymph nodes. At the time of diagnosis, shewas also found to have bony metastatic disease, and genetictesting revealed a deleterious 3036del4 germline BRCA2mutation. After multiple lines of therapy, including most

HindawiCase Reports in Oncological MedicineVolume 2018, Article ID 9529821, 5 pageshttps://doi.org/10.1155/2018/9529821

http://orcid.org/0000-0002-0234-5550https://doi.org/10.1155/2018/9529821

recently progressing on palbociclib and fulvestrant, thepatient was switched to monotherapy with olaparib. Her rashbegan approximately three days after starting olaparib cap-sules at a dose of 300mg twice daily. She subsequently devel-oped progression of the erythematous nodules which becamepainful and limited her ambulation, bilateral lower extremityedema, fevers to 101.7°F (degrees Fahrenheit), and rigors. Shetried diphenhydramine without any improvement in hersymptoms, and patient then presented to the emergencydepartment for evaluation. Her other home medicationsincluded levothyroxine, omeprazole, and cholecalciferol.

Her vital signs were within normal limits. Her physicalexamination revealed multiple erythematous nodules overthe bilateral distal lower extremities which were markedly

tender to palpation, along with trace edema in her bilaterallower extremities (Figure 1(a)). Her basic metabolic profilewas unremarkable, and her complete blood count demon-strated white blood count of 1.80 with absolute neutrophilcount of 1200, hemoglobin of 11.2, and platelet count of114. Her urinalysis was unremarkable, chest X-ray wasnormal, and blood cultures were sent. The patient was thenadmitted to inpatient Hematology-Oncology service forfurther evaluation of neutropenic fever. However, her infec-tious evaluation was unrevealing, and she then remainedafebrile off antibiotics. Since this patient’s symptoms andclinical examination were consistent with erythema nodo-sum, her olaparib was held. She was treated with nonsteroidalanti-inflammatory medications as well as acetaminophen as

(a) (b)

(c)

Figure 1: (a) Rash after initiation of olaparib therapy. (b) Recurrence of rash after the second course of treatment with olaparib. (c) Thirdrecurrence of rash after reinitiation of olaparib.

2 Case Reports in Oncological Medicine

needed for ongoing pain. She was discharged with close out-patient follow-up. Her nodules improved dramatically within24 hours of stopping olaparib and completely resolved withina week of withholding olaparib.

At her subsequent outpatient follow-up appointment,the patient was resumed on olaparib with a slow titrationof dose to her prior regimen of 300mg twice daily. Thefirst day she took the 300mg BID dose, the patient developedrecurrence of her erythema nodosum, and she was started ona course of prednisone with a resolution of her symptoms(Figure 1(b)). The patient was then restarted on olaparib ata reduced dose of 250mg twice daily, but afterwards devel-oped erythema nodosum again (Figure 1(c)). Her symptomsresolved after completing another short course of prednisonetherapy. At her next follow-up appointment, the patient waslater resumed on olaparib capsules at a dose of 200mg twicedaily. She has tolerated this therapy at a reduced dose withoutany significant recurrence of erythema nodosum requiringcessation of olaparib or use of prednisone therapy. Thispatient had a complete metabolic response to treatment inthe previously described metastatic bone lesions, and the pre-viously described focal liver FDG avidity was no longer seen;in addition, her CA27.29 normalized. Once olaparib tabletswere commercially available, she was subsequently changedto therapy with olaparib tablets 300mg twice daily. Sincethen, she similarly has continued to have intermittent butattenuated episodes of erythema that have not required treat-ment or cessation of therapy.

3. Discussion

As previously noted, FDA approval of olaparib capsules foruse in patients with ovarian cancer was based on the resultsof Study 19. Study 19 investigated olaparib as maintenancetherapy in patients with high-grade serous ovarian cancer,and this study did not require assessment of BRCA1/2 germ-line mutations. Eligible patients had completed at least twoprior platinum-based chemotherapy regimens with at leastpartial demonstrable response. The most frequent adverseevents reported leading to either dose reduction or holdingtherapy were vomiting, nausea, and fatigue. The study men-tioned one patient with the development of an erythematousrash necessitating cessation of olaparib therapy. However,this was deemed to be a grade 2 adverse event and no addi-tional information regarding the rash was included in thepublished paper [4]. More recently, the SOLO2 study waspublished which examined the efficacy of the olaparib tabletsfor maintenance treatment for relapsed ovarian cancerpatients with germline BRCA1 or BRCA2 mutations. Similarto what was evidenced in Study 19, the most common grade 3adverse event was anemia—affecting 19% of those in theolaparib arm and 2% in the placebo arm. There were noreported adverse events related to skin manifestations inthe study [6].

After the OlympiAD study’s publication, olaparib wassubsequently introduced into the treatment paradigm formetastatic breast cancer in patients with known germlineBRCA medications. Olaparib’s prior use in the treatmentof relapsed ovarian cancer affords some insight regarding

the potential adverse effects related to therapy [2]. How-ever, given its extension to a metastatic BRCA-positivebreast cancer patients, there remains a need for ongoingmonitoring for adverse effects in this new patient popula-tion. In the OlympiAD study, anemia was cited as themost frequent reason for dose reduction in patients pre-scribed olaparib; the reported frequency of anemia was40%, and dose reduction was necessitated in 13.7% ofpatients. The only adverse event with skin manifestationsreported in the main body of the article was palmar-plantarerythrodysesthesia—present in 0.5% of patients in the ola-parib group versus 20.9% of patients in the standard ther-apy group. However, in a review of the supplementalinformation for the OlympiAD study, one patient (0.5%)developed erythema nodosum requiring treatment discon-tinuation [5]. Therefore, our patient was unique in regardto continuing olaparib therapy after the development oferythema nodosum.

Erythema nodosum is well described as the most com-mon form of an uncommon condition—panniculitis orinflammation of the subcutaneous fat [7]. The characteristicpresentation of erythema nodosum is the onset of painful,erythematous nodules in the skin and subcutaneous tissues.These lesions are also typically elevated, approximately 1 to6 cm in diameter, and distributed throughout the bilaterallower extremities [8]. Patients frequently have associatedconstitutional symptoms—including fever, fatigue, andmalaise—and can also experience myalgia, headache, andabdominal pain [9]. Current practice guidelines do notnecessitate a biopsy to confirm the diagnosis in patients withclassic presentations [7].

There is currently no consensus for treatment of ery-thema nodosum, largely due to the uncommon nature ofthe condition. The majority of cases are self-limited, andpatients are provided with symptomatic management [7]. Itis reported that the majority of cases of erythema nodosumresolve within a few weeks—ranging from 3 to 4 weeks toup to 6 weeks for severe cases [8, 9]. The role for treatmentwith medications such as nonsteroidal anti-inflammatorymedications, potassium iodine therapy, or corticosteroids isbased on the reports of case reports or series [8, 10–12].

Erythema nodosum is categorized as a hypersensitivityresponse, and this can be as a response to a significant varietyof stimuli [9]. Although the exact immune-mediated mecha-nism has yet to be clearly elucidated, it has been postulated tobe due to a delayed hypersensitivity response [7]. A 1998French study reviewing the charts of 129 patients with con-firmed erythema nodosum demonstrated that 55% of caseswere idiopathic, and of the etiologies identified, the mostcommon were streptococcal infections (28%) and sarcoidosis(11%) [13]. In more recent years, drugs have emerged as acommon cause of erythema nodosum, with an extensive listof causative agents based on case reports—with more long-standing known offending agents including sulfonamideantibiotics and oral contraceptives [9].

Interestingly, the patient in our case report developederythema nodosum on both the olaparib tablet and cap-sule preparations, although her most severe episodes wereon the olaparib capsules at a dose of 300mg twice daily.

3Case Reports in Oncological Medicine

In a review of the prescribing information, the inactive ingre-dients for olaparib capsules are lauroyl polyoxylglycerides,hypromellose, titanium dioxide, gellan gum, potassium ace-tate, shellac, and ferrosoferric oxide [14]. The inactive ingre-dients for olaparib tablets include copovidone, mannitol,colloidal silicon dioxide, sodium stearyl fumarate, hypromel-lose, polyethylene glycol 400, titanium dioxide, and ferricoxide yellow for all dose strengths. In addition to what is pre-viously listed, the 150mg olaparib tablets also contain ferro-soferric oxide [15]. In a review of the pharmacokinetics, thebioavailability of the tablets is higher than capsules, andit was reported that the area under the curve (AUC) forpeople taking 300mg tablets twice daily was 77% higherwhen compared to those taking 400mg capsules twicedaily [15]. Finally, both preparations have different half-lives, with the mean half-life of the capsules and tablets11.0 and 14.9, respectively [14, 15]. A literature searchdid not reveal any articles associating the inactive ingredi-ents in both preparations—including hypromellose, gellangum, potassium acetate, lauroyl polyoxylglycerides, andshellac—with erythema nodosum.

In a review of the current literature, this is among thefirst reported cases of erythema nodosum due to olaparibtherapy and the first after the publication of the OlympiADstudy. Although dose is not usually related to erythemanodosum, it seemed to in this case as the patient’s erythemanodosum was most pronounced and symptomatic on ola-parib capsules at a dose of 300mg twice daily compared to200mg twice daily. There may be a dose-related off targeteffect of PARP inhibition on inflammation which warrantsmore investigation. In addition, the episodes occurred withtravel and stasis. She continued to have attenuated episodesof erythema nodosum on olaparib capsules at 200mg twicedaily as well as olaparib tablets 300mg twice daily. Giventhe higher bioavailability and longer half-life of the tabletscompared to capsule preparations, it is interesting that herskin findings and symptoms were less severe on the tablets300mg twice daily. However, it is possible that this is dueto the attenuation of the underlying hypersensitivityresponse over time.

4. Conclusion

The use of olaparib has only recently been incorporated intotreatment strategies for patients with germline BRCA1/2mutations with metastatic breast cancer. Although olaparibwas FDA approved for use in patients with BRCA mutationsand advanced ovarian carcinoma since December 2014, thiscase represents the second reported patient developing ery-thema nodosum while taking olaparib [3, 5]. Her symptoms,physical examination, and recurrence of rash with reintro-duction of olaparib on multiple occasions support the diag-nosis of erythema nodosum related to olaparib therapy.This case highlights the importance of monitoring for previ-ously undescribed adverse events while on novel therapies.Additionally, it also provides a strategy for managing ery-thema nodosum related to olaparib therapy that allows forreintroduction and maintenance with dose-reduced olaparibafter such an event.

Consent

Written informed consent was obtained from the patient forthe publication of this case report and any accompanyingimages.

Conflicts of Interest

Dr. Megan Wheelden, Dr. Leah Cream, and Dr. JeffreySivik declare that there is no conflict of interest regardingthe publication of this article. Dr. Mark Robson reportspersonal fees and nonfinancial support from AstraZenecaas part of the OlympiAD trial, grants from AbbVie andBioMarin/Medivation, and in-kind research support fromMyriad Genetics and Invitae.

References

[1] W. Rizvi, P. Truong, and Q. Truong, “Metastatic breast cancerwith BRCA mutation discovered by next-generation sequenc-ing responding to olaparib,” Cureus, vol. 9, no. 6, article e1337,2017.

[2] A. George, S. Banerjee, and S. Kaye, “Olaparib and somaticBRCA mutations,” Oncotarget, vol. 8, no. 27, pp. 43598-43599, 2017.

[3] G. Kim, G. Ison, A. E. McKee et al., “FDA approval summary:Olaparib monotherapy in patients with deleterious germlineBRCA-mutated advanced ovarian cancer treated with threeor more lines of chemotherapy,” Clinical Cancer Research,vol. 21, no. 19, pp. 4257–4261, 2015.

[4] J. Ledermann, P. Harter, C. Gourley et al., “Olaparib mainte-nance therapy in platinum-sensitive relapsed ovarian cancer,”The New England Journal of Medicine, vol. 366, no. 15,pp. 1382–1392, 2012.

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[6] E. Pujade-Lauraine, J. A. Ledermann, F. Selle et al., “Olaparibtablets as maintenance therapy in patients with platinum-sen-sitive, relapsed ovarian cancer and a BRCA1/2 mutation(SOLO2/ENGOT-Ov21): a double-blind, randomised, pla-cebo-controlled, phase 3 trial,” The Lancet Oncology, vol. 18,no. 9, pp. 1274–1284, 2017.

[7] T. Blake, M. Manahan, and K. Rodins, “Erythema nodosum –a review of an uncommon panniculitis,” Dermatology OnlineJournal, vol. 20, no. 4, 2014.

[8] J. Mana and J. Marcoval, “Erythema nodosum,” Clinics inDermatology, vol. 25, no. 3, pp. 288–294, 2007.

[9] L. Requena and E. SanchezYus, “Erythema nodosum,” Derma-tologic Clinics, vol. 26, no. 4, pp. 425–438, 2007.

[10] E. S. Friedman, N. LaNatra, and M. J. Stiller, “NSAIDs in der-matologic therapy: review and preview,” Journal of CutaneousMedicine and Surgery, vol. 6, no. 5, pp. 449–459, 2002.

[11] W. G. Barr and J. A. Robinson, “Chronic erythema nodosumtreated with indomethacin,” Annals of Internal Medicine,vol. 95, no. 5, p. 659, 1981.

[12] A. Mert, H. Kumbasar, R. Ozaras et al., “Erythema nodo-sum: an evaluation of 100 cases,” Clinical and ExperimentalRheumatology, vol. 25, no. 4, pp. 563–570, 2007.

4 Case Reports in Oncological Medicine

[13] B. Cribier, A. Caille, E. Heid, and E. Grosshans, “Erythemanodosum and associated diseases. A study of 129 cases,” Inter-national Journal of Dermatology, vol. 37, no. 9, pp. 667–672,1998.

[14] US Food and Drug Administration, “Highlights of prescribinginformation, Reference ID: 3675412,” 2014, https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdf.

[15] US Food and Drug Administration, “Highlights of prescrib-ing information, Reference ID: 4206580,” 2014, https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf.

5Case Reports in Oncological Medicine

https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206162lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s001lbl.pdf

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